Hypospadias, a congenital malformation in which the urethral opening is on the ventral side of the penis, is one of the most common congenital malformations. The main mechanisms believed to underlie hypospadias are environmental and genetic factors that impair maternal, fetal, or placental androgen and estrogen metabolism. However, the contribution of such factors to hypospadias risk has either not been evaluated or has largely been investigated with epidemiologic studies that have numerous limitations. We propose to address these shortcomings with a population-based nested case-control study of pesticides and candidate genes. This study will test the hypothesis that pesticides and candidate genes which interfere with maternal, fetal, or placental sex steroid metabolism affect hypospadias risk through the following specific aims: Aim 1 - Pesticides and hypospadias. We will determine whether maternal residential proximity to applications of agricultural pesticides around the time of urethral development is associated with increased hypospadias risk. We will examine individual pesticides as well as groupings of pesticides that have common physicochemical or functional properties. Aim 2 - Candidate genes and hypospadias. We will decipher the association between hypospadias risk and variants in 47 genes from the following mechanistic pathways important to urethral development: fetal and placental biosynthesis and biotransformation of sex steroid hormones, regulation of sex steroid hormone biosynthesis and action, and regulation of genital tubercle outgrowth and differentiation. These aims will be achieved by linking several sources of existing information: 1) detailed phenotypic data collected as part of a population-based, actively ascertained birth defects registry; 2) data from California pesticide-use reports; 3) newborn bloodspots collected as part of routine newborn screening; and 4) maternal and newborn descriptive characteristics from vital statistics. Thus, a critical strength of this proposal is that it will utilize epidemiologic data that were collected using rigorous case ascertainment and classification criteria and highly detailed data on exposures and covariates. The proposed research represents the first large-scale epidemiologic study to explore genetic and environmental exposures and hypospadias risk. This work will fill an important gap in our knowledge regarding the highly discussed but minimally studied association of endocrine-related exposures with hypospadias risk. Ultimately this research will provide valuable information about the causes of hypospadias and give avenues for preventive measures against this common congenital malformation. PUBLIC HEALTH RELEVANCE: The proposed research will improve our understanding of the causes of hypospadias. Its findings will contribute to the development of effective interventions or prevention messages, so that hypospadias can be prevented. While this malformation can be treated with surgery, it has a significant impact both on an individual's-and the overall public's-health, with long-term consequences such as impaired sexual function and psychosocial difficulties related to sexuality and sexual activity.